Why Does Hormonal Therapy Work So Well for Some Men?
Eisenberger: Mystery in advanced cancer
What is going on here? Something is mystifying to Mario Eisenberger, M.D., the R. Dale Hughes Professor of Oncology and Urology, and he wants to understand what’s happening, because he thinks the answer will bring help to men who desperately need it.
The puzzle has to do with advanced cancer. When prostate cancer is confined to the prostate, the best solution is a mechanical one — figure out the perimeter of the disease, and remove all cancer inside it. That becomes more difficult as the cancer spreads, and when it has set up outposts at distant sites, there is no way to say, “This area has cancer and I’m going to remove it,” because nobody knows exactly where all the cancer cells are. This brings us to Plan B: Finding something that prostate cancer cells have, and targeting that specifically.
The most obvious thing that prostate cancer cells have is androgen receptors; the prostate’s growth, from before birth, is driven by the presence of male hormones, called androgens. One way to shut down advanced cancer is to cut off its supply of these hormones; this is called “androgen deprivation therapy,” or hormonal therapy. In most men, when the hormones are gone, the PSA goes way down, there’s an improvement in symptoms, such as pain, and the cancer shrinks — but this remission doesn’t last. “Unfortunately, most patients progress,” says Eisenberger, “anywhere from around 18 months to four years.” In a few men, he notes, androgen deprivation therapy doesn’t work at all. “In these men, the disease progresses rapidly, and becomes fatal.”
But then there’s a third group. Not nearly as big as the first group, but Eisenberger has seen more of them in recent years. “These are men with advanced metastatic disease who respond dramatically to androgen deprivation therapy. Their disease seems to go away, and their remission is durable, lasting years longer than that of most men.”
These men, Eisenberger suspects, have distinctly different cancers — subtle genetic variations, or specific changes in their DNA that affect how they metabolize androgens — that somehow make them more susceptible to hormonal therapy. Working with a multidisciplinary team of Hopkins scientists, including Angelo De Marzo, Srinivasan Yegnasubramanian, Elizabeth Platz, Daniel Kejzman, Michael Carducci, Samuel Denmeade, Bruce Trock, Alan Partin, William Nelson, and Patrick Walsh, Eisenberger hopes to identify the secrets that give these men years longer than others who would seem to be in exactly the same situation.
“We will start by characterizing these three groups of men who develop metastatic disease after radical prostatectomy,” says Eisenberger, “their clinical, pathologic, and demographic factors,” looking for anything that sets them apart. They will look at the genetic makeup of these men, and look for possible new targets for treatment and, also, for ways to predict men whose disease is unlikely to respond to hormonal therapy, who can be spared its side effects, and directed to chemotherapy and other approaches.